An isothiocyanate group is a very useful functional group in synthetic organic chemistry since its reactivity is high and it can be led to various chemical structures. And, a carboxyl group is a useful functional group in the field of organic materials, drugs or agricultural chemicals because of its characteristic acidity and hydrogen bonding ability. Accordingly, an isothiocyanate compound having a carboxyl group(s), which has such two functional groups in one molecule, can be said to be a very useful compound as a product or a synthetic intermediate in the field of organic materials, drugs or agricultural chemicals. As an example, it is known that 3,5-diisothiocyanatobenzoic acid is useful as a starting material for the synthesis of a metal-binding polypeptide (e.g. Patent Document 1).
Various methods are known as methods for producing isothiocyanate compounds. Among them, a method for producing an isothiocyanate compound from an amino compound and carbon disulfide is a particularly useful method, since the carbon disulfide to be used is inexpensive, and the atom efficiency is good.
It is generally taken for granted that the method for synthesizing an isothiocyanate from an amino compound and carbon disulfide is suitable for the synthesis of an alkyl isothiocyanate but is inferior in the yield for an aryl isothiocyanate, and that the yield may be improved by using triethylamine as a basic catalyst, but by such a method, it is not possible to synthesize an aryl isothiocyanate having an electron-withdrawing group(s) (e.g. Non-Patent Document 1).
Further, the following methods of employing various additives in the reaction or in the reaction work-up have already been known as methods for synthesizing isothiocyanates. For example, a method of using ethyl chloroformate (Non-Patent Document 2), a method of using dicyclohexylcarbodiimide (Non-Patent Document 3), a method of using phosphorus oxychloride (Non-Patent Document 4), a method of using lead nitrate (Non-Patent Document 5), a method of using acetic anhydride (Patent Document 2), a method of using hydrogen peroxide (Non-Patent Document 6), a method of using sodium chloroacetate and zinc chloride (Non-Patent Document 7), a method of using iodine (Non-Patent Document 8), a method of using tosyl chloride (Non-Patent Document 9), etc. may be mentioned.
While there have been such many reports, there has been no report that an isothiocyanate compound having a carboxyl group(s) was produced by a method of using carbon disulfide and an additive(s) from the corresponding amino compound.
On the other hand, as a method for producing an isothiocyanate compound having the corresponding carboxyl group(s) from the corresponding amino compound, two cases have been reported, i.e. a method of using thiophosgene (Non-Patent Document 10) and a method of using tetramethylthiuram disulfide (Non-Patent Document 11). Among them, the method of using thiophosgene has a problem that thiophosgene itself has a very strong toxicity and bad odor. Further, the method of employing tetramethylthiuram disulfide has a problem that isolation of reaction intermediate is necessary, whereby the operation is cumbersome; the reaction condition is severe such that heating is carried out at a high temperature in the presence of acid; and tetramethylthiuram disulfide to be used is expensive. Therefore, it has been desired to develop a novel method for producing an isothiocyanate compound having a carboxyl group(s) in a high yield and with high purity without using such reagents, which is useful also as an industrial production method.
Patent Document 1: WO95/09013
Patent Document 2: JP-A-10-87605
Non-Patent Document 1: The Fifth Series of Experimental Chemistry, Vol.14 (2005) p.543-551, compiled by the Chemical Society of Japan.
Non-Patent Document 2: J. Am. Chem. Soc. (1958), 80, 3332
Non-Patent Document 3: Tetrahedron Asymm. (2006), 17, 999
Non-Patent Document 4: Tetrahedron(2003), 59, 4651
Non-Patent Document 5: Org. Synth. (1941), 1, 447
Non-Patent Document 6: Org. Synth. (1965), 45, 19
Non-Patent Document 7: J. Org. Chem. (1997), 62, 4539
Non-Patent Document 8: Collection of Czechoslovak Chem. Commun. (1985), 50, 2000
Non-Patent Document 9: J. Org. Chem. (2007), 72, 3969
Non-Patent Document 10: J. Am. Chem. Soc. (1946), 68, 2506
Non-Patent Document 11: Russ. Chem. Bull. (1999), 48, 739